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AIMS: This study investigated the effect of uptitration of sacubitril/valsartan (Sac/Val) compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level within current guideline-directed medical therapy in acute heart failure (AHF). METHODS AND RESULTS: This was the secondary analysis in the Program Angiotensin-Neprilysin Inhibition in Admitted Patients with Worsening Heart Failure (PREMIER) study. AHF patients were allocated to switch to Sac/Val or ACEIs/ARBs, and the Sac/Val group was divided into Sac/Val with or without uptitration group (Sac/Val >24/26 mg or ≤24/26 mg twice daily at week 8). The primary endpoint was the proportional change in geometric means of NT-proBNP levels at week 8. A total of 376 patients were included, consistent with the primary analysis in PREMIER. The percent changes in the NT-proBNP level were -51% (Sac/Val with uptitration), -39% (Sac/Val without uptitration), and -32% (ACEIs/ARBs). Their group ratios adjusted for baseline characteristics were 0.72 (Sac/Val with uptitration vs. ACEIs/ARBs, 95% confidence interval [CI], 0.59 to 0.89; P = .002) and 0.93 (Sac/Val without uptitration vs. ACEIs/ARBs, 95% CI, 0.76 to 1.13; P = .47). However, the Sac/Val without uptitration group yielded a greater NT-proBNP reduction than the ACEI/ARB group (adjusted ratio of change 0.72, 95% CI, 0.55 to 0.94; P = .016) in the subgroup of reduced ejection fraction. There were no adverse events associated with Sac/Val uptitration. CONCLUSIONS: Uptitration of Sac/Val therapy yielded a greater NT-proBNP level reduction in AHF patients, but Sac/Val therapy without uptitration also reduced NT-proBNP levels in a subgroup with reduced ejection fraction compared with ACEI/ARB therapy.